A multi-center study of ACE and the risk of late-onset Alzheimer's disease

Olivia Belbin, Kristelle Brown, Hui Shi, Christopher Medway, Richard Abraham, Peter Passmore, David Mann, A. David Smith, Clive Holmes, Bernadette McGuinness, David Craig, Donald Warden, Reinhard Heun, Heike Kölsch, Seth Love, Noor Kalsheker, Julie Williams, Michael J. Owen, Minerva M Carrasquillo, Steven G Younkin & 2 others Kevin Morgan, Patrick G. Kehoe

Research output: Contribution to journalArticle

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Abstract

A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies.

Original languageEnglish (US)
Pages (from-to)587-597
Number of pages11
JournalJournal of Alzheimer's Disease
Volume24
Issue number3
DOIs
StatePublished - 2011

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Peptidyl-Dipeptidase A
Alzheimer Disease
Haplotypes
Meta-Analysis
Case-Control Studies
Population
Population Characteristics
Amyloid
Logistic Models
Pharmacology
Pathology
Peptides
Enzymes
Genes

Keywords

  • Alzheimer's disease
  • angiotensin-1 converting enzyme
  • haplotype
  • heterogeneity
  • late onset
  • meta-analysis

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

Belbin, O., Brown, K., Shi, H., Medway, C., Abraham, R., Passmore, P., ... Kehoe, P. G. (2011). A multi-center study of ACE and the risk of late-onset Alzheimer's disease. Journal of Alzheimer's Disease, 24(3), 587-597. https://doi.org/10.3233/JAD-2011-101914

A multi-center study of ACE and the risk of late-onset Alzheimer's disease. / Belbin, Olivia; Brown, Kristelle; Shi, Hui; Medway, Christopher; Abraham, Richard; Passmore, Peter; Mann, David; Smith, A. David; Holmes, Clive; McGuinness, Bernadette; Craig, David; Warden, Donald; Heun, Reinhard; Kölsch, Heike; Love, Seth; Kalsheker, Noor; Williams, Julie; Owen, Michael J.; Carrasquillo, Minerva M; Younkin, Steven G; Morgan, Kevin; Kehoe, Patrick G.

In: Journal of Alzheimer's Disease, Vol. 24, No. 3, 2011, p. 587-597.

Research output: Contribution to journalArticle

Belbin, O, Brown, K, Shi, H, Medway, C, Abraham, R, Passmore, P, Mann, D, Smith, AD, Holmes, C, McGuinness, B, Craig, D, Warden, D, Heun, R, Kölsch, H, Love, S, Kalsheker, N, Williams, J, Owen, MJ, Carrasquillo, MM, Younkin, SG, Morgan, K & Kehoe, PG 2011, 'A multi-center study of ACE and the risk of late-onset Alzheimer's disease', Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 587-597. https://doi.org/10.3233/JAD-2011-101914
Belbin, Olivia ; Brown, Kristelle ; Shi, Hui ; Medway, Christopher ; Abraham, Richard ; Passmore, Peter ; Mann, David ; Smith, A. David ; Holmes, Clive ; McGuinness, Bernadette ; Craig, David ; Warden, Donald ; Heun, Reinhard ; Kölsch, Heike ; Love, Seth ; Kalsheker, Noor ; Williams, Julie ; Owen, Michael J. ; Carrasquillo, Minerva M ; Younkin, Steven G ; Morgan, Kevin ; Kehoe, Patrick G. / A multi-center study of ACE and the risk of late-onset Alzheimer's disease. In: Journal of Alzheimer's Disease. 2011 ; Vol. 24, No. 3. pp. 587-597.
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AU - Passmore, Peter

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